Nicotine depresses facial stimulation-evoked molecular layer interneuron-Purkinje cell synaptic transmission via α7 nicotinic acetylcholine receptors in mouse cerebellar cortex.

Nicotine modulates cerebellar physiology function by interacting with nicotinic acetylcholine receptors (nAChRs) and is involved in modulation of cerebellar cortical circuitry functions. Here, we investigated the effect of nicotine on sensory stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission mouse cerebellar cortex using in vivo cell-attached recording technique and pharmacological methods. The results show that micro-application of nicotine to the cerebellar molecular layer significantly decreased sensory stimulation-evoked MLI-PC synaptic transmission in mouse cerebellar cortex. Nicotine-induced depression in sensory stimulation-evoked MLI-PC synaptic transmission was abolished by either a non-selective nAChR blocker, hexamethonium, or the α7-nAChR antagonist methyllycaconitine (MLA), but not the selective α4ß2-nAChR antagonist dihydro-ß-erythroidine. Notably, molecular layer micro-application of nicotine did not significantly affect the number of spontaneous or facial stimulation-evoked action potentials of MLIs. Moreover, nicotine produced significant increases in the amplitude and frequency of miniature inhibitory postsynaptic currents of PCs, which were abolished by MLA in cerebellar slices. These results indicate that micro-application of nicotine to the cerebellar molecular layer depresses facial stimulation-induced MLI-PC synaptic transmission by activating α7 nAChRs, suggesting that cholinergic inputs modulate MLI-PC synapses to process sensory information in the cerebellar cortex of mice in vivo.

Suppression of SMOC2 reduces bleomycin (BLM)-induced pulmonary fibrosis by inhibition of TGF-ß1/SMADs pathway.

Although the initiation and modulation of lung fibrosis has been widely investigated, the pathogenesis was not well understood. Secreted modular calcium-binding protein 2 (SMOC2) as the secreted protein acidic is enriched in cysteine (SPARC) family of matricellular proteins, which are important in regulating cell-matrix interactions. Here we aimed to calculate the effects and molecular mechanism of SMOC2 on the progression and severity of lung fibrosis in murine bleomycin (BLM)-induced mice. The pulmonary fibrosis was significantly induced by BLM in wild type (WT) C57BL6 mice, as evidenced by the lung sections histology and collagen accumulation using H&E and Masson Trichrome staining. Notably, SMOC2 knockout (SMOC2-/-) mice treated with BLM exhibited the decrease in inflammation accompanied by the reduction of neutrophils, macrophages and lymphocytes in bronchoalveolar lavage fluids (BALF). In addition, the levels of inflammation-associated cytokines and chemokines induced by BLM were also decreased in BALF obtained from SMOC2-/- mice. Meanwhile, SMOC2-/- suppressed the progression of pulmonary fibrosis, as evidenced by the reduction in levels of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), p-SMAD2 and p-SMAD3 in lung tissue samples. Increasing expression of SMOC2 in TGF-ß1 treated cells were further observed in vitro. Of note, up regulation of SMOC2 activated-fibrosis development in MRC-5 cells, along with increase of α-SMA, p-SMAD2 and p-SMAD3 were determined. In contrast, SMOC2 knockdown reduced TGF-ß1-stimulated expressions of α-SMA, p-SMAD2 and p-SMAD3 in cells. The findings above suggested that SMOC2 knockout contributes to inhibit BLM-induced pulmonary fibrosis.